Amiodarone (hydrochloride)

Amiodarone is a class III antiarrhythmic agent, in that it prolongs both cardiac action potential and refractoriness by blocking potassium currents.¹ It inhibits the voltage-gated potassium channel hERG, also known as KCNH2, with an IC₅₀ value of 1 µM.² In addition, amiodarone binds with high affinity to the sigma-1 opioid receptor, 3-β-hydroxysteroid Δ⁸Δ⁷ isomerase, and C-8 sterol isomerase (K_is = 1, 25, and 62 nM, respectively) and inhibits human thyroid hormone receptors α and β (IC₅₀s = 0.6, 0.65 µM, respectively).^3,4 It also inhibits the cytochrome P450 (CYP) isoforms CYP2C8 and CYP3A4 in vitro at low micromolar concentrations.⁵

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1. Campbell, T.J., and Williams, K.M. Therapeutic drug monitoring: Antiarrhythmic drugs. Br. J. Clin. Pharmacol. 46(4), 307-319 (1998).

2. Sinha, N., and Sen, S. Predicting hERG activities of compounds from their 3D structures: Development and evaluation of a global descriptors based QSAR model. Eur. J. Med. Chem. 46(2), 618-630 (2011).

3. Laggner, C., Schieferer, C., Fiechtner, B., et al. Discovery of high-affinity ligands of σ1 receptor, ERG2, and emopamil binding protein by pharmacophore modeling and virtual screening. J. Med. Chem. 48(15), 4754-4764 (2005).

4. Carlsson, B., Singh, B.N., Temciuc, M., et al. Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone. J. Med. Chem. 45(3), 623-630 (2002).

5. Polasek, T.M., Elliott, D.J., Lewis, B.C., et al. Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro. J. Pharmacol. Exp. Ther. 311(3), 996-1007 (2004).